The mammalian gastrointestinal tract contains the largest number of immune cells and harbors a large and diverse population of commensal bacteria that exist in a symbiotic relationship with the host.1,2 The gut-resident immune cells are separated from our microbial residents by a single layer of intestinal epithelial cells (IEC). The dynamic cross-talk between IEC, the intestinal microbiota, and local immune cells represents a cornerstone of intestinal homeostasis.3,4 The balance between the various immune cell populations and tonic cytokine signals play an important role in determining thresholds of tolerance and immunity in the intestine.
We recently highlighted the relevance of Oncostatin M (OSM) in intestinal inflammation.5 OSM is a pleiotropic cytokine belonging to the interleukin 6 (IL-6) family, which influences numerous homoeostatic and pathological processes in various organs, yet its biology remains obscure.6,7 OSM receptor (OSMR) is widely expressed at both tissue (vascular system, heart, lung, adipose tissue, skin, bladder, mammary tissue, adrenal gland, and prostate) and cellular levels (endothelial, smooth muscle, fibroblast, and lung epithelial cells). In contrast, OSM is expressed in multiple hematopoietic cell types including activated monocytes/macrophages, neutrophils, dendritic cells, and T cells. We showed recently that OSMR is widely expressed by stromal and endothelial cells in the intestine; however, the role of OSM in the maintenance of intestinal homeostasis remains unknown. We hypothesize that microbiota-derived local cues induce constitutive OSM expression by gut-resident immune cells to promote intestinal homeostasis by acting on both stromal and endothelial cell compartments. This project will exploit new reporter mouse lines generated in Hegazy lab (OsmriScarlet, OsmZsgreen), gnotobiotic mice, and primary human tissue samples to explore the signals regulating OSM expression in the gut and how OSM functions as a potential tissue rheostat. The project will utilize different cellular and molecular biology techniques, including magnetic cell isolation, flow cytometry, gene expression analysis, RNA sequencing, and histology.
The following specific objectives will be addressed in this project: